PIMOZIDE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C28H29F2N3O
Molecular Weight	461.5462
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

FC1=CC=C(C=C1)C(CCCN2CCC(CC2)N3C(=O)NC4=CC=CC=C34)C5=CC=C(F)C=C5

InChI

InChIKey=YVUQSNJEYSNKRX-UHFFFAOYSA-N

InChI=1S/C28H29F2N3O/c29-22-11-7-20(8-12-22)25(21-9-13-23(30)14-10-21)4-3-17-32-18-15-24(16-19-32)33-27-6-2-1-5-26(27)31-28(33)34/h1-2,5-14,24-25H,3-4,15-19H2,(H,31,34)

HIDE SMILES / InChI

Molecular Formula	C28H29F2N3O
Molecular Weight	461.5462
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/017473s046lbl.pdf
Curator's Comment: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/10762666

Pimozide (Orap) is a diphenylbutylpiperidine that is effective as an antipsychotic agent and as an alternative to haloperidol for the suppression of vocal and motor tics in patients with Tourette syndrome. It is not intended as a treatment of first choice nor is it intended for the treatment of tics that are merely annoying or cosmetically troublesome. It should be reserved for use in Tourette’s Disorder patients whose development and/or daily life function is severely compromised by the presence of motor and phonic tics. Evidence supporting approval of pimozide for use in Tourette’s Disorder was obtained in two controlled clinical investigations, which enrolled patients between the ages of 8 and 53 years. Most subjects in the two trials were 12 or older. Pimozide is an orally active antipsychotic drug product, which shares with other antipsychotics the ability to blockade dopaminergic receptors on neurons in the central nervous system. Although its exact mode of action has not been established, the ability of pimozide to suppress motor and phonic tics in Tourette’s Disorder is thought to be a function of its dopaminergic blocking activity. However, receptor blockade is often accompanied by a series of secondary alterations in central dopamine metabolism and function which may contribute to both pimozide’s therapeutic and untoward effects. In addition, pimozide, in common with other antipsychotic drugs, has various effects on other central nervous system receptor systems which are not fully characterized.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
HERG 92 Target ID: CHEMBL240 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11511086	Inhibitor 8297		18.0 nM [IC50]
Dopamine receptor 60 Target ID: CHEMBL2096905 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8301582	Antagonist 2778

Conditions

Condition	Modality	Targets	Highest Phase	Product
Tourette's syndrome 20 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/017473s046lbl.pdf	Palliative		Approved 8429	ORAP Approved Use INDICATIONS & USAGE Pimozide Tablets, USP is indicated for the suppression of motor and phonic tics in patients with Tourette’s Disorder who have failed to respond satisfactorily to standard treatment. Pimozide Tablets, USP is not intended as a treatment of first choice nor is it intended for the treatment of tics that are merely annoying or cosmetically troublesome. Pimozide Tablets, USP should be reserved for use in Tourette’s Disorder patients whose development and/or daily life function is severely compromised by the presence of motor and phonic tics. Evidence supporting approval of Pimozide Tablets, USP for use in Tourette’s Disorder was obtained in two controlled clinical investigations which enrolled patients between the ages of 8 and 53 years. Most subjects in the two trials were 12 or older. Launch Date 1984

AUC

Value	Dose	Co-administered	Analyte	Population
0.261 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3480904	2 mg single, oral dose: 2 mg route of administration: Oral experiment type: SINGLE co-administered:		PIMOZIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
0.347 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3480904	2 mg single, oral dose: 2 mg route of administration: Oral experiment type: SINGLE co-administered:		PIMOZIDE plasma	Homo sapiens population: UNHEALTHY age: CHILD sex: MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
109 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3480904	2 mg single, oral dose: 2 mg route of administration: Oral experiment type: SINGLE co-administered:		PIMOZIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
57 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3480904	2 mg single, oral dose: 2 mg route of administration: Oral experiment type: SINGLE co-administered:		PIMOZIDE plasma	Homo sapiens population: UNHEALTHY age: CHILD sex: MALE food status: FASTED

Doses

Dose	Population	Adverse events
6 mg 1 times / day single, oral Overdose Dose: 6 mg, 1 times / day Route: oral Route: single Dose: 6 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/15641643/	healthy, 1.5 n = 1 Health Status: healthy Age Group: 1.5 Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/15641643/	Other AEs: Tremor, Tongue thrust... Other AEs: Tremor Tongue thrust Drooling Drowsiness Slow response to stimuli Blood pressure decreased Sources: https://pubmed.ncbi.nlm.nih.gov/15641643/
100 mg 1 times / day single, oral Overdose Dose: 100 mg, 1 times / day Route: oral Route: single Dose: 100 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/824116/	healthy, 17 n = 1 Health Status: healthy Age Group: 17 Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/824116/	Other AEs: Tremor... Other AEs: Tremor Sources: https://pubmed.ncbi.nlm.nih.gov/824116/
0.2 mg/kg 1 times / day multiple, oral Recommended Dose: 0.2 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.2 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/6371107/	unhealthy, 2-13 n = 20 Health Status: unhealthy Condition: Tourette's syndrome Age Group: 2-13 Sex: M+F Population Size: 20 Sources: https://pubmed.ncbi.nlm.nih.gov/6371107/	Disc. AE: Akathisia, Akinesia... AEs leading to discontinuation/dose reduction: Akathisia Akinesia Sources: https://pubmed.ncbi.nlm.nih.gov/6371107/
800 mg 1 times / day single, oral Overdose Dose: 800 mg, 1 times / day Route: oral Route: single Dose: 800 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/15641643/	healthy, 53 n = 1 Health Status: healthy Age Group: 53 Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/15641643/	Other AEs: Torsades de pointes, Electrocardiogram QTc interval prolonged... Other AEs: Torsades de pointes Electrocardiogram QTc interval prolonged Sources: https://pubmed.ncbi.nlm.nih.gov/15641643/
21 mg 1 times / day multiple, oral Highest studied dose Dose: 21 mg, 1 times / day Route: oral Route: multiple Dose: 21 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/4214674/	unhealthy, adult n = 51 Health Status: unhealthy Condition: chronic schizophrenia Age Group: adult Sex: M+F Population Size: 51 Sources: https://pubmed.ncbi.nlm.nih.gov/4214674/	Sources: https://pubmed.ncbi.nlm.nih.gov/4214674/

AEs

AE	Significance	Dose	Population
Blood pressure decreased		6 mg 1 times / day single, oral Overdose Dose: 6 mg, 1 times / day Route: oral Route: single Dose: 6 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/15641643/	healthy, 1.5 n = 1 Health Status: healthy Age Group: 1.5 Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/15641643/
Drooling		6 mg 1 times / day single, oral Overdose Dose: 6 mg, 1 times / day Route: oral Route: single Dose: 6 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/15641643/	healthy, 1.5 n = 1 Health Status: healthy Age Group: 1.5 Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/15641643/
Drowsiness		6 mg 1 times / day single, oral Overdose Dose: 6 mg, 1 times / day Route: oral Route: single Dose: 6 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/15641643/	healthy, 1.5 n = 1 Health Status: healthy Age Group: 1.5 Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/15641643/
Slow response to stimuli		6 mg 1 times / day single, oral Overdose Dose: 6 mg, 1 times / day Route: oral Route: single Dose: 6 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/15641643/	healthy, 1.5 n = 1 Health Status: healthy Age Group: 1.5 Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/15641643/
Tongue thrust		6 mg 1 times / day single, oral Overdose Dose: 6 mg, 1 times / day Route: oral Route: single Dose: 6 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/15641643/	healthy, 1.5 n = 1 Health Status: healthy Age Group: 1.5 Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/15641643/
Tremor		6 mg 1 times / day single, oral Overdose Dose: 6 mg, 1 times / day Route: oral Route: single Dose: 6 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/15641643/	healthy, 1.5 n = 1 Health Status: healthy Age Group: 1.5 Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/15641643/
Tremor		100 mg 1 times / day single, oral Overdose Dose: 100 mg, 1 times / day Route: oral Route: single Dose: 100 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/824116/	healthy, 17 n = 1 Health Status: healthy Age Group: 17 Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/824116/
Akathisia	Disc. AE	0.2 mg/kg 1 times / day multiple, oral Recommended Dose: 0.2 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.2 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/6371107/	unhealthy, 2-13 n = 20 Health Status: unhealthy Condition: Tourette's syndrome Age Group: 2-13 Sex: M+F Population Size: 20 Sources: https://pubmed.ncbi.nlm.nih.gov/6371107/
Akinesia	Disc. AE	0.2 mg/kg 1 times / day multiple, oral Recommended Dose: 0.2 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.2 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/6371107/	unhealthy, 2-13 n = 20 Health Status: unhealthy Condition: Tourette's syndrome Age Group: 2-13 Sex: M+F Population Size: 20 Sources: https://pubmed.ncbi.nlm.nih.gov/6371107/
Electrocardiogram QTc interval prolonged		800 mg 1 times / day single, oral Overdose Dose: 800 mg, 1 times / day Route: oral Route: single Dose: 800 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/15641643/	healthy, 53 n = 1 Health Status: healthy Age Group: 53 Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/15641643/
Torsades de pointes		800 mg 1 times / day single, oral Overdose Dose: 800 mg, 1 times / day Route: oral Route: single Dose: 800 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/15641643/	healthy, 53 n = 1 Health Status: healthy Age Group: 53 Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/15641643/

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737		substrate 1217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461 L-type Ca2+ channels 28 T-type Ca2+ channels 3	CYP1A2 1054 P-gp 1537

Drug as perpetrator

Target	Modality	Activity
L-type Ca2+ channels 30	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/2160063/	yes
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/30275188/	yes
T-type Ca2+ channels 3	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29202456/	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/017473Orig1s046.pdf Page: 9, 15	major
CYP1A2 1054	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/017473Orig1s046.pdf Page: 9.0	minor
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/017473Orig1s046.pdf Page: 9, 10, 15	minor	yes (co-administration study) Comment: coadministration with paroxetine resulted in a 151% increase in pimozide AUC and 62% increase in pimozide Cmax. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/017473Orig1s046.pdf Page: 9, 10, 15
P-gp 1537	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/33119612/	yes

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:8212	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:8212
ChemicalBook	CB7290660	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB7290660
MolPort	MolPort-001-736-597	https://www.molport.com/shop/molecule-link/MolPort-001-736-597
ZINC	ZINC000004175630	http://zinc15.docking.org/substances/ZINC000004175630
eMolecules	593283	https://www.emolecules.com/cgi-bin/more?vid=593283

PubMed

Title	Date	PubMed
Pimozide-induced depression associated with polyuria and polydipsia.	1992 Apr	1307220
Pharmacology of human dopamine D3 receptor expressed in a mammalian cell line: comparison with D2 receptor.	1992 Apr 10	1354163
Use of pimozide in the Pisa syndrome.	1992 Aug	1322069
Subjective response to antipsychotic treatment and compliance in schizophrenia. A naturalistic study comparing olanzapine, risperidone and haloperidol (EFESO Study).	2001	11835695
Pharmacological options for the treatment of Tourette's disorder.	2001	11772131
Gilles de la Tourette syndrome in a child with congenital deafness.	2001 Dec	11794551
Agonist, antagonist, and inverse agonist properties of antipsychotics at human recombinant 5-HT(1A) receptors expressed in HeLa cells.	2001 Dec 14	11755134
Quetiapine for tic disorder: a case report.	2001 Nov	11853307
Antipsychotic-related QTc prolongation, torsade de pointes and sudden death.	2002	12109926
Effects of psychotropic drugs on seizure threshold.	2002	11888352
Delusional parasitosis in leprosy.	2002 Apr-Jun	12708735
The Ca(2+) channel antagonists mibefradil and pimozide inhibit cell growth via different cytotoxic mechanisms.	2002 Aug	12130671
A comparison of the receptor binding and HERG channel affinities for a series of antipsychotic drugs.	2002 Aug 16	12176106
The effects of long-term testosterone, gonadotropin-releasing hormone agonist and pimozide treatments on testicular development and luteinizing hormone levels in juvenile and early maturing striped bass, Morone saxatilis.	2002 Dec	12460602
Neuroleptic withdrawal versus serotonergic syndrome in an 8-year-old child.	2002 Fall	12427301
Atypical antipsychotics: mechanism of action.	2002 Feb	11873706
Differential inhibition of T-type calcium channels by neuroleptics.	2002 Jan 15	11784784
The treatment of Tourette's syndrome: current opinions.	2002 Jul	12083990
Potassium channel antagonists influence porcine granulosa cell proliferation, differentiation, and apoptosis.	2002 Jul	12080003
Trigeminal neuralgia.	2002 Jun	12230739
Seasonal short-term effects of naltrexone on LH secretion in male carp (Cyprinus carpio L.).	2002 Mar	11912062
Psychotropic drugs and the ECG: focus on the QTc interval.	2002 May	11996627
[Tic syndrome].	2002 May-Jun	12185806
Obesity and related metabolic abnormalities during antipsychotic drug administration: mechanisms, management and research perspectives.	2002 Nov	12518268
[Delusions of parasitosis: An up-to-date review].	2002 Oct	12376915
Na(+)/Ca(2+) exchanger in porcine oocytes.	2002 Oct	12297528
The role of nutrition in the regulation of LH secretion during anestrus by the serotoninergic and dopaminergic systems in Mediterranean ewes treated with melatonin.	2002 Oct 15	12387344
[Chronic tic disorders--chronic mortor or vocal tic disorders and de la Tourette's syndrome].	2003	14626066
QTc prolongation due to propranolol overdose.	2003	12968835
Drug interactions of clinical significance for the dermatologist: recognition and avoidance.	2003	12926981
Lopinavir/ritonavir: a review of its use in the management of HIV infection.	2003	12662125
Corticotropin-releasing factor as well as opioid and dopamine are involved in tail-pinch-induced food intake of rats.	2003	12559107
Noradrenergic modulation of ephedrine-induced hypophagia.	2003 Apr	12557268
Cav3.1 (alpha1G) T-type Ca2+ channels mediate vaso-occlusion of sickled erythrocytes in lung microcirculation.	2003 Aug 22	12869394
Zebrafish embryos express an orthologue of HERG and are sensitive toward a range of QT-prolonging drugs inducing severe arrhythmia.	2003 Dec 15	14678746
P300 changes in major depressive disorders with and without psychotic features.	2003 Feb	12547298
Antipsychotic augmentation for treatment resistant obsessive-compulsive disorder: what if antipsychotic is discontinued?	2003 Jan	12490771
Antipsychotic medication and seizures: a review.	2003 Jul	12973403
[A case of delusional parasitosis in severe heart failure. Olanzapine within the framework of a multimodal therapy].	2003 Jul	12861369
Pimozide injections into the Nucleus accumbens disrupt maternal behaviour in lactating rats.	2003 Jul	12828573
Cannabinoid pharmacological properties common to other centrally acting drugs.	2003 Jun 27	12826237
Detection of proarrhythmia in the female rabbit heart: blinded validation.	2003 Mar	12716112
Screening, library-assisted identification and validated quantification of fifteen neuroleptics and three of their metabolites in plasma by liquid chromatography/mass spectrometry with atmospheric pressure chemical ionization.	2003 Mar	12644990
Pimozide: use in dermatology.	2003 Mar	12639456
Biphasic role of dopamine on female sexual behaviour via D2 receptors in the mediobasal hypothalamus.	2003 Mar	12604086
8-[3H]-hydroxy-2-(di-n-propylamino)tetralin binding sites in blood lymphocytes of rats and the modulation by mitogens and immobilization.	2003 May	12742647
Cytotoxicity of conventional and atypical antipsychotic drugs in relation to glucose metabolism.	2003 May 2	12691834
Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome p450 3A4 substrate, in patients with chronic myeloid leukaemia.	2003 Nov 17	14612892
Tic reduction with risperidone versus pimozide in a randomized, double-blind, crossover trial.	2004 Feb	14726728
T-type calcium channels in the regulation of afferent and efferent arterioles in rats.	2004 Feb	14583435

Patents

Sample Use Guides

In Vivo Use Guide

Children: Treatment should be initiated at a dose of 0.05 mg/kg preferably taken once at bedtime. The dose may be increased every third day to a maximum of 0.2 mg/kg not to exceed 10 mg/day. Adults: treatment should be initiated with a dose of 1 to 2 mg a day in divided doses. The dose may be increased thereafter every other day. Most patients are maintained at less than 0.2 mg/kg/day, or 10 mg/day, whichever is less. Doses greater than 0.2 mg/kg/day or 10 mg/day are not recommended. At doses above 4 mg/day, CYP 2D6 genotyping should be performed. In poor CYP 2D6 metabolizers, doses should not exceed 4 mg/day, and doses should not be increased earlier than 14 days.

Route of Administration: Oral

In Vitro Use Guide

Pimozide (PMZD) (10 uM) had minimal effect on Kv1.4, and had no effect on the M-current candidates, KCNQ2 and KCNQ3 when co-expressed in Xenopus oocytes. In hippocampal neurons, PMZD inhibited the delayed rectifiers by approximately 60%, and A-type currents were insensitive to PMZD. The results suggest that PMZD inhibits certain neuronal Kv channels in heterologous expression systems and in hippocampal neurons. PMZD was less effective on A-type currents, presumably because its ability to block requires a prolonged opening of the K channels.

Substance Class	Chemical Created by `admin` on `Sat Dec 16 17:29:47 GMT 2023` Edited by `admin` on `Sat Dec 16 17:29:47 GMT 2023`
Record UNII	1HIZ4DL86F
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

PIMOZIDE

Official Name

English

ORAP

Brand Name

English

PIMOZIDE [USP MONOGRAPH]

Common Name

English

PIMOZIDE [ORANGE BOOK]

Common Name

English

MCN-JR-6238

Code

English

Pimozide [WHO-DD]

Common Name

English

2H-BENZIMIDAZOL-2-ONE, 1-(1-(4,4-BIS(4-FLUOROPHENYL)BUTYL)-4-PIPERIDINYL)-1,3-DIHYDRO

Common Name

English

PIMOZIDE [USAN]

Common Name

English

NSC-170984

Code

English

PIMOZIDE [MART.]

Common Name

English

PIMOZIDE [JAN]

Common Name

English

PIMOZIDE [EP MONOGRAPH]

Common Name

English

pimozide [INN]

Common Name

English

1-[1-[4,4-Bis(4-fluorophenyl)butyl]-4-piperidyl]-2-benzimidazolinone

Systematic Name

English

R 623

Code

English

PIMOZIDE [MI]

Common Name

English

PIMOZIDE [VANDF]

Common Name

English

R-6238

Code

English

PIMOZIDE [USP-RS]

Common Name

English

R-623

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C29710